Phenobarbital for Alcohol Withdrawal - Revision history

LiamG: /* Dose titration */

2024-10-07T20:39:23Z

Dose titration

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 : The standard 260mg/130mg regimen works well for average size patients.  This regimen yields weight-based doses of 3.7 mg/kg and 1.9 mg/kg in a 70 kg patient.  However, for patients substantially below or above 70 kg, clinicians should consider administering 4 mg/kg with subsequent doses of 2 mg/kg.  For convenience, these doses can be rounded to the nearest 130 mg increment (i.e. the amount in a single vial).  For example, weight-based doing for a 125 kg patient would yield 500 mg and 250 mg doses, and these can be safely rounded to 520mg and 260mg for ease of administration.  Weight-based dosing prevents sedating unusually small patients while preventing excessively long visits for unusually large patients.  Dosing in whole-vial increments minimizes the risk of dosing errors and eliminates the effort required to precisely dose from a 1mL vial.
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 === Dosing interval ===

AndyS: /* Toxicology */

2019-09-24T17:06:05Z

Toxicology

← Older revision		Revision as of 17:06, 24 September 2019
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	:PB blood levels above 80 μg/mL are considered "potentially" lethal, whereas lethal overdose is usually associated with levels of 100-200 μg/mL.<ref name = "PBpkginsert"/> For a 70 kg person, these levels would result from ingestions of 3,394mg, 4,242mg, and 8,485mg, respectively. Six to ten grams is a commonly cited lethal ingestion dose range.<ref>Lindberg MC, Cunningham A, Lindberg NH. Acute phenobarbital intoxication. South Med J. 1992;85(8):803-807. doi:[https://doi.org/10.1097/00007611-199208000-00004 10.1097/00007611-199208000-00004]</ref><ref name = "Hoyland2013">Hoyland K, Hoy M, Austin R, Wildman M. Successful use of haemodialysis to treat phenobarbital overdose. BMJ Case Rep. 2013;2013. doi:[https://doi.org/10.1136/bcr-2013-010011 10.1136/bcr-2013-010011]</ref>		:PB blood levels above 80 μg/mL are considered "potentially" lethal, whereas lethal overdose is usually associated with levels of 100-200 μg/mL.<ref name = "PBpkginsert"/> For a 70 kg person, these levels would result from ingestions of 3,394mg, 4,242mg, and 8,485mg, respectively. Six to ten grams is a commonly cited lethal ingestion dose range.<ref>Lindberg MC, Cunningham A, Lindberg NH. Acute phenobarbital intoxication. South Med J. 1992;85(8):803-807. doi:[https://doi.org/10.1097/00007611-199208000-00004 10.1097/00007611-199208000-00004]</ref><ref name = "Hoyland2013">Hoyland K, Hoy M, Austin R, Wildman M. Successful use of haemodialysis to treat phenobarbital overdose. BMJ Case Rep. 2013;2013. doi:[https://doi.org/10.1136/bcr-2013-010011 10.1136/bcr-2013-010011]</ref>

	:~~Management~~ is generally supportive: airway maintenance/protection, mechanical ventilation, volume and vasopressors as needed for circulatory support.		:Overdose management is generally supportive: airway maintenance/protection, mechanical ventilation, volume and vasopressors as needed for circulatory support.

	:The is no PB/BBT antidote. Due to the extremely long half-life of PB, hemodialysis is often used to rapidly decrease serum levels.<ref name = "Hoyland2013"/>		:The is no PB/BBT antidote. Due to the extremely long half-life of PB, hemodialysis is often used to rapidly decrease serum levels.<ref name = "Hoyland2013"/>

AndyS: /* Toxicology */

2019-09-24T17:05:15Z

Toxicology

← Older revision		Revision as of 17:05, 24 September 2019
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	=== Toxicology ===		=== Toxicology ===
	:PB blood levels above 80 μg/mL are considered "potentially" lethal, whereas lethal overdose is usually associated with levels of 100-200 μg/mL.<ref name = "PBpkginsert"/> For a 70 kg person, these levels would result from ingestions of 3,394mg, 4,242mg, and 8,485mg, respectively. Six to ten grams is a commonly cited lethal ingestion dose range.<ref>Lindberg MC, Cunningham A, Lindberg NH. Acute phenobarbital intoxication. South Med J. 1992;85(8):803-807. doi:[https://doi.org/10.1097/00007611-199208000-00004 10.1097/00007611-199208000-00004]</ref><ref>Hoyland K, Hoy M, Austin R, Wildman M. Successful use of haemodialysis to treat phenobarbital overdose. BMJ Case Rep. 2013;2013. doi:[https://doi.org/10.1136/bcr-2013-010011 10.1136/bcr-2013-010011]</ref>		:PB blood levels above 80 μg/mL are considered "potentially" lethal, whereas lethal overdose is usually associated with levels of 100-200 μg/mL.<ref name = "PBpkginsert"/> For a 70 kg person, these levels would result from ingestions of 3,394mg, 4,242mg, and 8,485mg, respectively. Six to ten grams is a commonly cited lethal ingestion dose range.<ref>Lindberg MC, Cunningham A, Lindberg NH. Acute phenobarbital intoxication. South Med J. 1992;85(8):803-807. doi:[https://doi.org/10.1097/00007611-199208000-00004 10.1097/00007611-199208000-00004]</ref><ref name = "Hoyland2013">Hoyland K, Hoy M, Austin R, Wildman M. Successful use of haemodialysis to treat phenobarbital overdose. BMJ Case Rep. 2013;2013. doi:[https://doi.org/10.1136/bcr-2013-010011 10.1136/bcr-2013-010011]</ref>

			:Management is generally supportive: airway maintenance/protection, mechanical ventilation, volume and vasopressors as needed for circulatory support.

			:The is no PB/BBT antidote. Due to the extremely long half-life of PB, hemodialysis is often used to rapidly decrease serum levels.<ref name = "Hoyland2013"/>
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AndyS: Formatting only.

2019-09-24T16:45:20Z

Formatting only.

← Older revision		Revision as of 16:45, 24 September 2019
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	== ~~'''~~Treatment Principles and Pearls~~'''~~ ==		== Treatment Principles and Pearls ==
	=== Sub-sedative dosing ===		=== Sub-sedative dosing ===
	: Alcohol withdrawal is a ''hyper''-alert and/or ''hyper''-autonomic state. The goal of outpatient treatment of alcohol withdrawal is ''normalization'' of alertness (i.e. level of consciousness) and autonomic function, not sedation. If a sedative level of [any] medication is required for AWS symptom control, then admission is often indicated.		: Alcohol withdrawal is a ''hyper''-alert and/or ''hyper''-autonomic state. The goal of outpatient treatment of alcohol withdrawal is ''normalization'' of alertness (i.e. level of consciousness) and autonomic function, not sedation. If a sedative level of [any] medication is required for AWS symptom control, then admission is often indicated.
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	== ~~'''~~Evidence of Effectiveness and Safety~~'''~~ ==		== Evidence of Effectiveness and Safety ==
	=== Systematic Review / Meta-analysis ===		=== Systematic Review / Meta-analysis ===
	* A 2016 systematic review by '''Mo et al'''. in the ''Journal of Critical Care''<ref name="Mo2016" /> concluded that "''barbiturates alone or in combination with BZDs are at least as effective as BZDs in the treatment of AWS. Furthermore, barbiturates appear to have acceptable tolerability and safety profiles, which were similar to those of BZDs in patients with AWS.''" This review included three randomized controlled trials (RCT's) and four observational studies. Importantly, the authors observed that "''none of these studies demonstrated inferiority of barbiturates to BZDs in the management of AWS.''" While this review firmly establishes PB's similar pharmacological effectiveness compared to BZD's, only one of the included studies (an RCT by Hendey et al.<ref name="Hendey2011">Hendey GW, Dery RA, Barnes RL, Snowden B, Mentler P. A prospective, randomized, trial of phenobarbital versus benzodiazepines for acute alcohol withdrawal. Am J Emerg Med. 2011;29(4):382-385. doi:[https://doi.org/10.1016/j.ajem.2009.10.010 10.1016/j.ajem.2009.10.010]</ref>) focused solely upon outpatient treatment. Though its sample size was small (25 in PB group, 19 in BZD group), Hendey et al. reported statistically nonsignificant trends toward better outcomes in the PB group.		* A 2016 systematic review by '''Mo et al'''. in the ''Journal of Critical Care''<ref name="Mo2016" /> concluded that "''barbiturates alone or in combination with BZDs are at least as effective as BZDs in the treatment of AWS. Furthermore, barbiturates appear to have acceptable tolerability and safety profiles, which were similar to those of BZDs in patients with AWS.''" This review included three randomized controlled trials (RCT's) and four observational studies. Importantly, the authors observed that "''none of these studies demonstrated inferiority of barbiturates to BZDs in the management of AWS.''" While this review firmly establishes PB's similar pharmacological effectiveness compared to BZD's, only one of the included studies (an RCT by Hendey et al.<ref name="Hendey2011">Hendey GW, Dery RA, Barnes RL, Snowden B, Mentler P. A prospective, randomized, trial of phenobarbital versus benzodiazepines for acute alcohol withdrawal. Am J Emerg Med. 2011;29(4):382-385. doi:[https://doi.org/10.1016/j.ajem.2009.10.010 10.1016/j.ajem.2009.10.010]</ref>) focused solely upon outpatient treatment. Though its sample size was small (25 in PB group, 19 in BZD group), Hendey et al. reported statistically nonsignificant trends toward better outcomes in the PB group.
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	== ~~'''~~Regulatory Information and Packaging~~'''~~ ==		== Regulatory Information and Packaging ==
	*PB is not approved by the U.S. FDA; this is likely due its use preceding the creation of the FDA (in 1938).		*PB is not approved by the U.S. FDA; this is likely due its use preceding the creation of the FDA (in 1938).
	*DEA Schedule: IV		*DEA Schedule: IV
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	== ~~'''~~Pharmacology~~'''~~ ==		== Pharmacology ==
	<br />		<br />
	The following are some of the important properties of PB with regard to outpatient treatment of AWS.<br />		The following are some of the important properties of PB with regard to outpatient treatment of AWS.<br />
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	::::::# Increased duration of channel opening. This contrasts with the effect of BZDs, which is increased frequency of channel opening.<ref name="Hobbs1996" /><br />		::::::# Increased duration of channel opening. This contrasts with the effect of BZDs, which is increased frequency of channel opening.<ref name="Hobbs1996" /><br />
	::Both 2 and 3 indicate a potential additive (or even synergistic) effect when co-administered with BZDs in severe withdrawal. This is consistent with statistically nonsignificant trends in published studies.<ref name="Mo2016" />		::Both 2 and 3 indicate a potential additive (or even synergistic) effect when co-administered with BZDs in severe withdrawal. This is consistent with statistically nonsignificant trends in published studies.<ref name="Mo2016" />
			<br />
	:; Glutamate antagonist		:; Glutamate antagonist
	::The binding of glutamate to its receptor stimulates nerve depolarization. At sub-sedative doses PB/BBTs also inhibit the AMPA subtype of glutamate receptors; however, PB/BBT do not effect the NMDA subtype.<ref name="Hobbs1996" /> This glutamate antagonism is an anti-convulsive effect which is separate from PB's GABAergic effect.<ref>Nardou R, Yamamoto S, Bhar A, Burnashev N, Ben-Ari Y, Khalilov I. Phenobarbital but Not Diazepam Reduces AMPA/kainate Receptor Mediated Currents and Exerts Opposite Actions on Initial Seizures in the Neonatal Rat Hippocampus. Front Cell Neurosci. 2011;5:16. doi:[https://doi.org/10.3389/fncel.2011.00016 10.3389/fncel.2011.00016]</ref>		::The binding of glutamate to its receptor stimulates nerve depolarization. At sub-sedative doses PB/BBTs also inhibit the AMPA subtype of glutamate receptors; however, PB/BBT do not effect the NMDA subtype.<ref name="Hobbs1996" /> This glutamate antagonism is an anti-convulsive effect which is separate from PB's GABAergic effect.<ref>Nardou R, Yamamoto S, Bhar A, Burnashev N, Ben-Ari Y, Khalilov I. Phenobarbital but Not Diazepam Reduces AMPA/kainate Receptor Mediated Currents and Exerts Opposite Actions on Initial Seizures in the Neonatal Rat Hippocampus. Front Cell Neurosci. 2011;5:16. doi:[https://doi.org/10.3389/fncel.2011.00016 10.3389/fncel.2011.00016]</ref>
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	=== Distribution ===		=== Distribution ===
	~~<br />~~
	==== Venous concentration versus infused dose ====		==== Venous concentration versus infused dose ====
	{\| class="wikitable" style="float:right;font-size: 85%; border: 1px solid black;"		{\| class="wikitable" style="float:right;font-size: 85%; border: 1px solid black;"
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	[[File:PB_CSF_pharmacokinetics_01.PNG\|center\|thumb\|500px\|'''Fig-1. Adult phenobarbital brain concentration versus time after a rapid bolus injection'''. Y-axis is fractional concentration compared to the initial serum concentration (which has been removed for clarity). Adapted from Fig-3 of Paulson 1982<ref name = "Paulson1982"/>]]		[[File:PB_CSF_pharmacokinetics_01.PNG\|center\|thumb\|500px\|'''Fig-1. Adult phenobarbital brain concentration versus time after a rapid bolus injection'''. Y-axis is fractional concentration compared to the initial serum concentration (which has been removed for clarity). Adapted from Fig-3 of Paulson 1982<ref name = "Paulson1982"/>]]
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	::~~However~~, the manufacturer package insert (updated 12-10-2018) states that peak brain concentration is reached within 15 minutes of IV administration.<ref name = "PBpkginsert"/>		::Alternately, the manufacturer package insert (updated 12-10-2018) states that peak brain concentration is reached within 15 minutes of IV administration.<ref name = "PBpkginsert"/>
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	== ~~'''~~Abbreviations~~'''~~ ==		== Abbreviations ==
	:'''AWS''': Alcohol Withdrawal Syndrome		:'''AWS''': Alcohol Withdrawal Syndrome
	:'''BBT''': Barbiturate[s]		:'''BBT''': Barbiturate[s]
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	== ~~'''~~Related Topics~~'''~~ ==		== Related Topics ==
	''[[Alcohol Withdrawal in the YK Delta]]''		''[[Alcohol Withdrawal in the YK Delta]]''
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	== ~~'''~~External Links~~'''~~ ==		== External Links ==
	PubMed (all settings):		PubMed (all settings):
	:[https://www.ncbi.nlm.nih.gov/pubmed/?term=%22alcohol+withdrawal%22%5BTitle%2FAbstract%5D+AND+(phenobarb%5BTitle%2FAbstract%5D+OR+barbiturat%5BTitle%2FAbstract%5D) "alcohol withdrawal"[Title/Abstract<nowiki>]</nowiki> AND (phenobarb[Title/Abstract<nowiki>]</nowiki> OR barbiturat[Title/Abstract<nowiki>]</nowiki>)]		:[https://www.ncbi.nlm.nih.gov/pubmed/?term=%22alcohol+withdrawal%22%5BTitle%2FAbstract%5D+AND+(phenobarb%5BTitle%2FAbstract%5D+OR+barbiturat%5BTitle%2FAbstract%5D) "alcohol withdrawal"[Title/Abstract<nowiki>]</nowiki> AND (phenobarb[Title/Abstract<nowiki>]</nowiki> OR barbiturat[Title/Abstract<nowiki>]</nowiki>)]
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	== ~~'''~~Contributors~~'''~~ ==		== Contributors ==
	''Authors''		''Authors''
	:Andrew W. Swartz, MD<br />		:Andrew W. Swartz, MD<br />
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	== ~~'''~~References~~'''~~ ==		== References ==
	<references />		<references />

AndyS: /* Cautions */

2019-09-23T18:57:29Z

Cautions

← Older revision		Revision as of 18:57, 23 September 2019
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	:Airway obstruction		:Airway obstruction
	:Respiratory distress		:Respiratory distress
			:Significant blood level of alcohol or other sedatives
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AndyS at 18:54, 23 September 2019

2019-09-23T18:54:37Z

← Older revision		Revision as of 18:54, 23 September 2019
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	::::::# Enhancement of the binding of BZDs<ref name="Hobbs1996" /><br />		::::::# Enhancement of the binding of BZDs<ref name="Hobbs1996" /><br />
	::::::# Increased duration of channel opening. This contrasts with the effect of BZDs, which is increased frequency of channel opening.<ref name="Hobbs1996" /><br />		::::::# Increased duration of channel opening. This contrasts with the effect of BZDs, which is increased frequency of channel opening.<ref name="Hobbs1996" /><br />
	::Both 2 and 3 indicate a potential synergistic effect when co-administered with BZDs. ~~Studies have shown that dual therapy~~ is ~~superior to either PB or BZDs alone,(insert refs) indicating at least an additive effect~~.		::Both 2 and 3 indicate a potential additive (or even synergistic) effect when co-administered with BZDs in severe withdrawal. This is consistent with statistically nonsignificant trends in published studies.<ref name="Mo2016" />
	:; Glutamate antagonist		:; Glutamate antagonist
	::The binding of glutamate to its receptor stimulates nerve depolarization. At sub-sedative doses PB/BBTs also inhibit the AMPA subtype of glutamate receptors; however, PB/BBT do not effect the NMDA subtype.<ref name="Hobbs1996" /> This glutamate antagonism is an anti-convulsive effect which is separate from PB's GABAergic effect.<ref>Nardou R, Yamamoto S, Bhar A, Burnashev N, Ben-Ari Y, Khalilov I. Phenobarbital but Not Diazepam Reduces AMPA/kainate Receptor Mediated Currents and Exerts Opposite Actions on Initial Seizures in the Neonatal Rat Hippocampus. Front Cell Neurosci. 2011;5:16. doi:[https://doi.org/10.3389/fncel.2011.00016 10.3389/fncel.2011.00016]</ref>		::The binding of glutamate to its receptor stimulates nerve depolarization. At sub-sedative doses PB/BBTs also inhibit the AMPA subtype of glutamate receptors; however, PB/BBT do not effect the NMDA subtype.<ref name="Hobbs1996" /> This glutamate antagonism is an anti-convulsive effect which is separate from PB's GABAergic effect.<ref>Nardou R, Yamamoto S, Bhar A, Burnashev N, Ben-Ari Y, Khalilov I. Phenobarbital but Not Diazepam Reduces AMPA/kainate Receptor Mediated Currents and Exerts Opposite Actions on Initial Seizures in the Neonatal Rat Hippocampus. Front Cell Neurosci. 2011;5:16. doi:[https://doi.org/10.3389/fncel.2011.00016 10.3389/fncel.2011.00016]</ref>
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	:Megan Young, MD		:Megan Young, MD
	:Travis Nelson, MD		:Travis Nelson, MD
	:Tara Lathrop, MD		:Tara Lathrop, MD (Emergency Department Service Chief)
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AndyS at 18:35, 23 September 2019

2019-09-23T18:35:38Z

← Older revision		Revision as of 18:35, 23 September 2019
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	<br /><br />		<br /><br />
	The treatment of AWS with phenobarbital (or barbiturates [BBT] in general) is not new, but it has fallen so out of favor that many clinicians are unfamiliar with this use. However, there is ample published evidence, both old and new, indicating that phenobarbital is ''at least'' equally safe and effective compared with benzodiazepines.		The treatment of AWS with phenobarbital (or barbiturates [BBT] in general) is not new, but it has fallen so out of favor that many clinicians are unfamiliar with this use. However, there is ample published evidence, both old and new, indicating that phenobarbital is ''at least'' equally safe and effective compared with benzodiazepines.
			<br /><br />
			This page focuses upon the use and pharmacology of phenobarbital. For more general information about AWS and local practices, see ''[[Alcohol Withdrawal in the YK Delta]]''.
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	: When patients’ hyper-alert/hyper-autonomic state is normalized, many will lightly nap. But such patients easily awaken to voice or light touch and they easily meet all discharge criteria. Rather than being “sedated,” such patients are merely exhibiting the normal physiologic response in the absence of discomfort to a 24-48 hour sleep deficit (which is the norm for patients in this situation). Any concern for sedation can usually be answered by asking oneself if the patient’s post-treatment behavior would be considered '''ab'''normal for a patient in the ED with a normal mental status, with a substantial sleep deficit, whose discomfort had been relieved. If the answer is “no”, then the patient is not “sedated,” but rather has been returned to a normal level of alertness.		: When patients’ hyper-alert/hyper-autonomic state is normalized, many will lightly nap. But such patients easily awaken to voice or light touch and they easily meet all discharge criteria. Rather than being “sedated,” such patients are merely exhibiting the normal physiologic response in the absence of discomfort to a 24-48 hour sleep deficit (which is the norm for patients in this situation). Any concern for sedation can usually be answered by asking oneself if the patient’s post-treatment behavior would be considered '''ab'''normal for a patient in the ED with a normal mental status, with a substantial sleep deficit, whose discomfort had been relieved. If the answer is “no”, then the patient is not “sedated,” but rather has been returned to a normal level of alertness.
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	=== ~~Post~~-infusion ~~dizziness/nystagmus/ataxia~~ ===		=== Transient post-infusion effects ===
	:~~Post-infusion dizziness~~/nystagmus/ataxia is a common, transient effect of IV PB administration. Both experience and published reports reveal that this resolves spontaneously in 15-30 minutes. Given PB's exceptionally long half-life, this seems to be attributable to the rapidity of the drug level increase rather than the level itself. After resolution, this is not a contraindication for more PB, but further doses should be infused much more slowly (such as over 30-45 minutes). Importantly, this is not an allergic reaction nor a reaction which warrants a chart alert. This reaction can be thought of as similar to the "red man" effect of vancomycin: it merely requires adjustment of the administration speed and possibly the dosing interval. This effect occurs more frequently when infusing larger doses (such as 390mg or 520mg) over 10 minutes; such larger doses (such as in a very large patient or one with a well-established dose requirement) should be infused over 30-45 minutes.		:;Dizziness/nystagmus/ataxia
			::This is a common, transient effect of IV PB administration. Both experience and published reports reveal that this resolves spontaneously in 15-30 minutes. Given PB's exceptionally long half-life, this seems to be attributable to the rapidity of the drug level increase rather than the level itself. After resolution, this is not a contraindication for more PB, but further doses should be infused much more slowly (such as over 30-45 minutes). Importantly, this is not an allergic reaction nor a reaction which warrants a chart alert. This reaction can be thought of as similar to the "red man" effect of vancomycin: it merely requires adjustment of the administration speed and possibly the dosing interval. This effect occurs more frequently when infusing larger doses (such as 390mg or 520mg) over 10 minutes; such larger doses (such as in a very large patient or one with a well-established dose requirement) should be infused over 30-45 minutes.
			:;Asymptomatic hypotension
			::One study (Young et al.<ref name = "Young1987">Young GP, Rores C, Murphy C, Dailey RH. Intravenous phenobarbital for alcohol withdrawal and convulsions. Ann Emerg Med. 1987;16(8):847-850. doi:[https://doi.org/10.1016/s0196-0644(87)80520-6 10.1016/s0196-0644(87)80520-6]</ref>) reported that 1 of 62 patients treated with IV PB monotherapy ''"had an asymptomatic blood pressure fall to 90/60 mm Hg, which rose without intervention within 30 minutes."''
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			=== Post-treatment tiredness ===
			:Once symptom control has been achieved with PB, most patients complain of feeling "tired". It is unclear if this is an effect of phenobarbital versus an appropriate sensation given their physiologic circumstance. Regardless of etiology, tiredness seems a good indicator that they will be able to sleep.
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	~~=== Alcoholic Hallucinosis ===~~
	: Alcoholic hallucinosis (AH), also known as Alcohol Induced Psychotic Disorder, is described as persistent hallucinations ''without other strong evidence of alcohol withdrawal or alcohol delirium''. Hallucinations are predominantly auditory though can be visual and can be accompanied by delusions and suicidality. AH is a heterogeneous disorder with variable presentation and clinical course. Hallucinosis typically lasts 2-7 days, though persistent hallucinosis lasting weeks to months is possible.

	: As AH is a relatively rare phenomenon there is not consensus in the literature regarding treatment. Two approaches are generally utilized. The first approach considers alcoholic hallucinosis as a symptom of alcohol withdrawal, with treatment utilizing GABA agonists. The second approach considers alcoholic hallucinosis as a primary psychotic disorder treated with either first or second generation antipsychotics. Both approaches appear equally efficacious, though data is limited by a lack of single studies comparing treatments via a randomized approach.

	: A reasonable approach is to treat for alcohol withdrawal as long as symptoms of withdrawal persist, then adjunct treatment with a second generation antipsychotic if hallucinosis persists after other withdrawal symptoms have improved. Providers are cautioned against the use of anti-psychotics during DTs as these are associated with increased mortality, likely via QT prolongation and lowering of seizure threshold.<ref>Masood B, Lepping P, Romanov D, Poole R. Treatment of Alcohol-Induced Psychotic Disorder (Alcoholic Hallucinosis)-A Systematic Review. Alcohol Alcohol. 2018;53(3):259-267. doi:[https://doi.org/10.1093/alcalc/agx090 10.1093/alcalc/agx090]</ref>
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	== '''Evidence of Effectiveness and Safety''' ==		== '''Evidence of Effectiveness and Safety''' ==
	=== Systematic Review / Meta-analysis ===		=== Systematic Review / Meta-analysis ===
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	=== Studies of ED/Outpatient Treatment ===		=== Studies of ED/Outpatient Treatment ===
	* '''Young et al'''. (1987, prospective uncontrolled study, n=62)<ref name = "Young1987"~~>Young GP, Rores C, Murphy C, Dailey RH. Intravenous phenobarbital for alcohol withdrawal and convulsions. Ann Emerg Med. 1987;16(8):847-850. doi:[https:~~/~~/doi.org/10.1016/s0196-0644(87)80520-6 10.1016/s0196-0644(87)80520-6]</ref~~><br />		* '''Young et al'''. (1987, prospective uncontrolled study, n=62)<ref name = "Young1987"/><br />
	::62 patients received IV PB loading dose in the emergency department. The protocol was an initial 260mg which was followed by 130mg increments, but the dosing interval is unclear. The mean loading dose was 598 mg (8.4 mg/kg) and the subsequent mean serum PB level was 13.9 mcg/mL. Four patients experienced minor, self-limited adverse reactions (asymptomatic hypotension, ataxia, or lethargy) which resolved without intervention. All patients were discharged from the ED and none returned for further care during the following week.		::62 patients received IV PB loading dose in the emergency department. The protocol was an initial 260mg which was followed by 130mg increments, but the dosing interval is unclear. The mean loading dose was 598 mg (8.4 mg/kg) and the subsequent mean serum PB level was 13.9 mcg/mL. Four patients experienced minor, self-limited adverse reactions (asymptomatic hypotension, ataxia, or lethargy) which resolved without intervention. All patients were discharged from the ED and none returned for further care during the following week.

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	[[File:PB_CSF_pharmacokinetics_01.PNG\|center\|thumb\|500px\|'''Fig-1. Adult phenobarbital brain concentration versus time after a rapid bolus injection'''. Y-axis is fractional concentration compared to the initial serum concentration (which has been removed for clarity). Adapted from Fig-3 of Paulson 1982<ref name = "Paulson1982"/>]]		[[File:PB_CSF_pharmacokinetics_01.PNG\|center\|thumb\|500px\|'''Fig-1. Adult phenobarbital brain concentration versus time after a rapid bolus injection'''. Y-axis is fractional concentration compared to the initial serum concentration (which has been removed for clarity). Adapted from Fig-3 of Paulson 1982<ref name = "Paulson1982"/>]]
	<br />		<br />
	However, the manufacturer package insert (updated 12-10-2018) states that peak brain concentration is reached within 15 minutes of IV administration.<ref name = "PBpkginsert"/>		::However, the manufacturer package insert (updated 12-10-2018) states that peak brain concentration is reached within 15 minutes of IV administration.<ref name = "PBpkginsert"/>
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	=== Bioavailability ===		=== Bioavailability ===
	Intramuscular bioavailability is 75-80% (based upon a 1978 study of five young adult males<ref>Viswanathan CT, Booker HE, Welling PG. Bioavailability of oral and intramuscular phenobarbital. J Clin Pharmacol. 1978;18(2-3):100-105. PMID:[https://www.ncbi.nlm.nih.gov/pubmed/624773 624773]</ref>).		:Intramuscular bioavailability is 75-80% (based upon a 1978 study of five young adult males<ref>Viswanathan CT, Booker HE, Welling PG. Bioavailability of oral and intramuscular phenobarbital. J Clin Pharmacol. 1978;18(2-3):100-105. PMID:[https://www.ncbi.nlm.nih.gov/pubmed/624773 624773]</ref>).
	<br />		<br />
	<br />		<br />
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	:'''PB''': Phenobarbital		:'''PB''': Phenobarbital
	:'''YKDRH''': Yukon-Kuskokwim Delta Regional Hospital		:'''YKDRH''': Yukon-Kuskokwim Delta Regional Hospital
			<br />
			<br />

			== '''Related Topics''' ==
			''[[Alcohol Withdrawal in the YK Delta]]''
	<br />		<br />
	<br />		<br />
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	''Authors''		''Authors''
	:Andrew W. Swartz, MD<br />		:Andrew W. Swartz, MD<br />
	~~:Travis Nelson, MD <br />~~
	''Reviewers:''		''Reviewers:''
	:Megan Young, MD		:Megan Young, MD
			:Travis Nelson, MD
	:Tara Lathrop, MD		:Tara Lathrop, MD
	<br />		<br />

AndyS: /* Contributors */

2019-09-23T00:36:15Z

Contributors

← Older revision		Revision as of 00:36, 23 September 2019
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	''Authors''		''Authors''
	:Andrew W. Swartz, MD<br />		:Andrew W. Swartz, MD<br />
			:Travis Nelson, MD <br />
	''Reviewers:''		''Reviewers:''
	~~:Travis Nelson, MD (suggestions incorporated)~~
	:Megan Young, MD		:Megan Young, MD
	:Tara Lathrop, MD		:Tara Lathrop, MD

AndyS: /* Distribution */

2019-09-23T00:33:53Z

Distribution

← Older revision		Revision as of 00:33, 23 September 2019
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	=== Distribution ===		=== Distribution ===

	~~:Volume of distribution is X(ref).~~

	~~:Plasma protein binding has been estimated as X percent, predominantly to albumin.(ref)~~
	<br />		<br />
	==== Venous concentration versus infused dose ====		==== Venous concentration versus infused dose ====
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	<br />		<br />
	<br />		<br />

	=== Bioavailability ===		=== Bioavailability ===
	Intramuscular bioavailability is 75-80% (based upon a 1978 study of five young adult males<ref>Viswanathan CT, Booker HE, Welling PG. Bioavailability of oral and intramuscular phenobarbital. J Clin Pharmacol. 1978;18(2-3):100-105. PMID:[https://www.ncbi.nlm.nih.gov/pubmed/624773 624773]</ref>).		Intramuscular bioavailability is 75-80% (based upon a 1978 study of five young adult males<ref>Viswanathan CT, Booker HE, Welling PG. Bioavailability of oral and intramuscular phenobarbital. J Clin Pharmacol. 1978;18(2-3):100-105. PMID:[https://www.ncbi.nlm.nih.gov/pubmed/624773 624773]</ref>).

AndyS at 00:17, 23 September 2019

2019-09-23T00:17:34Z

← Older revision		Revision as of 00:17, 23 September 2019
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	:Post-infusion dizziness/nystagmus/ataxia is a common, transient effect of IV PB administration. Both experience and published reports reveal that this resolves spontaneously in 15-30 minutes. Given PB's exceptionally long half-life, this seems to be attributable to the rapidity of the drug level increase rather than the level itself. After resolution, this is not a contraindication for more PB, but further doses should be infused much more slowly (such as over 30-45 minutes). Importantly, this is not an allergic reaction nor a reaction which warrants a chart alert. This reaction can be thought of as similar to the "red man" effect of vancomycin: it merely requires adjustment of the administration speed and possibly the dosing interval. This effect occurs more frequently when infusing larger doses (such as 390mg or 520mg) over 10 minutes; such larger doses (such as in a very large patient or one with a well-established dose requirement) should be infused over 30-45 minutes.		:Post-infusion dizziness/nystagmus/ataxia is a common, transient effect of IV PB administration. Both experience and published reports reveal that this resolves spontaneously in 15-30 minutes. Given PB's exceptionally long half-life, this seems to be attributable to the rapidity of the drug level increase rather than the level itself. After resolution, this is not a contraindication for more PB, but further doses should be infused much more slowly (such as over 30-45 minutes). Importantly, this is not an allergic reaction nor a reaction which warrants a chart alert. This reaction can be thought of as similar to the "red man" effect of vancomycin: it merely requires adjustment of the administration speed and possibly the dosing interval. This effect occurs more frequently when infusing larger doses (such as 390mg or 520mg) over 10 minutes; such larger doses (such as in a very large patient or one with a well-established dose requirement) should be infused over 30-45 minutes.
	<br />		<br />
	~~=== Isolated withdrawal hallucinosis ===~~
	: A subset of AWS patients will present as soon as 12 hours after alcohol cessation with classic withdrawal hallucinations but without any signs of hyper-alertness, clouding of consciousness, confusion, or autonomic hyper-stimulation. This is a well documented variant of AWS, and it should be neither under-treated (i.e. dismissed as fake) nor over-treated (i.e. managed as delirium tremens). Hallucinations are one of the many manifestations of AWS, and they can occur in isolation or in combination with other signs. Primary management is a therapeutic level of GABA agonist (i.e. PB or a BZD). The use of anti-psychotic medications is contraversial. If hallucinations are refractory to an appropriate level of GABA agonist then an anti-psychotic medication can be added. However, caution is advised because there have been reports of increased mortality associated with these medications due to arrhythmias (due to QT prolongation) and lowering the seizure threshold. The risk/benefit must be carefully weighted in these situations, especially in the first 48 hours when the seizure risk is highest. Anti-psychotic medications should never be the first-line or sole therapy for hallucinosis or other withdrawal symptoms.<ref>Jesse S, Bråthen G, Ferrara M, et al. Alcohol withdrawal syndrome: mechanisms, manifestations, and management. Acta Neurol Scand. 2017;135(1):4-16. doi:[https://doi.org/10.1111/ane.12671 10.1111/ane.12671].</ref>
	~~<br />~~
	~~<br />~~


	=== Alcoholic Hallucinosis ===		=== Alcoholic Hallucinosis ===
			: Alcoholic hallucinosis (AH), also known as Alcohol Induced Psychotic Disorder, is described as persistent hallucinations ''without other strong evidence of alcohol withdrawal or alcohol delirium''. Hallucinations are predominantly auditory though can be visual and can be accompanied by delusions and suicidality. AH is a heterogeneous disorder with variable presentation and clinical course. Hallucinosis typically lasts 2-7 days, though persistent hallucinosis lasting weeks to months is possible.

	: ~~Alcoholic hallucinosis (~~AH~~), also known as Alcohol Induced Psychotic Disorder,~~ is ~~described~~ as ~~persistent hallucinations without other strong evidence~~ of alcohol withdrawal ~~or alcohol delirium~~. ~~Hallucinations are predominantly auditory though can be visual and can be accompanied by delusions and suicidality. AH is~~ a ~~heterogeneous~~ disorder with ~~variable presentation and clinical course~~. ~~Hallucinosis typically lasts 2-7 days~~, though ~~persistent hallucinosis lasting weeks to months~~ is ~~possible~~.		: As AH is a relatively rare phenomenon there is not consensus in the literature regarding treatment. Two approaches are generally utilized. The first approach considers alcoholic hallucinosis as a symptom of alcohol withdrawal, with treatment utilizing GABA agonists. The second approach considers alcoholic hallucinosis as a primary psychotic disorder treated with either first or second generation antipsychotics. Both approaches appear equally efficacious, though data is limited by a lack of single studies comparing treatments via a randomized approach.

			: A reasonable approach is to treat for alcohol withdrawal as long as symptoms of withdrawal persist, then adjunct treatment with a second generation antipsychotic if hallucinosis persists after other withdrawal symptoms have improved. Providers are cautioned against the use of anti-psychotics during DTs as these are associated with increased mortality, likely via QT prolongation and lowering of seizure threshold.<ref>Masood B, Lepping P, Romanov D, Poole R. Treatment of Alcohol-Induced Psychotic Disorder (Alcoholic Hallucinosis)-A Systematic Review. Alcohol Alcohol. 2018;53(3):259-267. doi:[https://doi.org/10.1093/alcalc/agx090 10.1093/alcalc/agx090]</ref>
	: As AH is a relatively rare phenomenon there is not consensus in the literature regarding treatment. Two approaches are generally utilized. The first approach considers alcoholic hallucinosis as a symptom of alcohol withdrawal, with treatment utilizing gaba agonists. The second approach considers alcoholic hallucinosis as a primary psychotic disorder treated with either first or second generation antipsychotics. Both approaches appear equally efficacious, though data is limited by a lack of single studies comparing treatments via a randomized approach.		<br />


	: A reasonable approach is to treat for alcohol withdrawal as long as symptoms of withdrawal persist, then adjunct treatment with a second generation antipsychotic if hallucinosis persists after other withdrawal symptoms have improved. Providers are cautioned against the use of anti-psychotics during DTs as these are associated with increased mortality, likely via QT prolongation and lowering of seizure threshold.



	~~[[media:Barkat_et_al_2017~~.~~pdf\|~~Treatment of Alcohol Induced Psychotic Disorder]]

	== '''Evidence of Effectiveness and Safety''' ==		== '''Evidence of Effectiveness and Safety''' ==